We continue a research program which includes basic studies of the clinical pharmacology of abused drugs and novel treatment strategies. Our approach is multidisciplinary, including psychiatry, psychology, pharmacology, neurology, and chemistry, and involves only human subjects. An administrative and laboratory core component (I) provides cost- effective shared resources. Project II addresses the determinants of individual differences in pharmacologic responses to caffeine and differences in caffeine self-administration. It attempts to understand caffeine use patterns in drug-dependent patients. Project IV continues clinical investigations of the interplay between cocaine use, depression and opiate detoxification. Psychopharmacologic treatments for depression, cocaine and concurrent opiate use will be contrasted with treatment of patients with primary cocaine dependence and those with mixed patterns of opiate and cocaine use and in patients with significant alcohol co-morbidity. Project V investigates in patients with neuropathic pain the efficacy and effects of various opioid analgesics with particular attention to tolerance and related phenomena that occur with repeated exposure to opioid drugs. Importance of route of administration and dose and tolerance development will be determined. Project VI will characterize the behavior of newborn infants born of mothers using cocaine and other psychoactive drugs (including caffeine, nicotine and alcohol) to better understand the syndromes associated with neonatal intoxication and drug withdrawal. Project VII tests the hypothesis that environmental lead exposure is an important factor to consider in understanding the etiology of developmental problems in high risk, newborn infants. Project VIII investigates the interactions between alcohol and cocaine. Possible mechanisms, both pharmacokinetic and pharmacodynamic and particularly those relevant to understanding toxicity, will be characterized as will the kinetics of the homolog, cocaethylene, its effects and contribution to the mix of enhanced and diminished effects of ethanol and of cocaine when taken in combination. In each project, relationships between behavioral, physiologic and pharmacologic variables are of interest. In all the studies, biochemical, psychophysiologic, behavioral and psychometric techniques are used to assess the consequences of acute and/or chronic drug use. The research will further the understanding, mechanisms and treatment of disorders associated with human psychoactive drug use.